EP0488210B1 - Process for preparing 1,5-benzothiazepine derivative - Google Patents

Process for preparing 1,5-benzothiazepine derivative Download PDF

Info

Publication number
EP0488210B1
EP0488210B1 EP91120269A EP91120269A EP0488210B1 EP 0488210 B1 EP0488210 B1 EP 0488210B1 EP 91120269 A EP91120269 A EP 91120269A EP 91120269 A EP91120269 A EP 91120269A EP 0488210 B1 EP0488210 B1 EP 0488210B1
Authority
EP
European Patent Office
Prior art keywords
acetic acid
hydroxy
compound
methoxyphenyl
dihydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP91120269A
Other languages
German (de)
French (fr)
Other versions
EP0488210A1 (en
Inventor
Masanori Yoshioka
Mitsuyoshi Wagatsma
Akiyoshi Yoda
Yoshihisa Yamada
Gunji Yoshimura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tanabe Seiyaku Co Ltd
Original Assignee
Tanabe Seiyaku Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tanabe Seiyaku Co Ltd filed Critical Tanabe Seiyaku Co Ltd
Publication of EP0488210A1 publication Critical patent/EP0488210A1/en
Application granted granted Critical
Publication of EP0488210B1 publication Critical patent/EP0488210B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a process for preparing hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one which is useful as a medicinal compound.
  • Hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (hereinafter referred to as desired compound), particularly, d-cis form thereof is a medicinal compound useful as a coronary vasodilator and an anti-hypertensive agent. Hitherto, there have been known some processes for preparing the desired compound.
  • Examples of these processes are, for instance, (1) a process wherein 3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (hereinafter referred to as 3-hydroxy compound) is reacted with an acetylating agent such as acetic anhydride with heating to give 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (hereinafter referred to 3-acetoxy compound) according to a conventional method and then the resulting 3-acetoxy compound is treated with ethanolic hydrogen chloride (or methanolic hydrogen chloride) (see Japanese Examined Patent Publication No.
  • 3-hydroxy compound 3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)eth
  • An object of the invention is to provide a process for simply preparing the desired compound from the 3-hydroxy compound in one step without cooling the reaction system or using a large excess of an acetylating agent.
  • the above-mentioned process of the present invention is established based upon a novel knowledge that acetyl chloride acts as not only an acetylating agent for the 3-hydroxy compound but also a supplier of hydrogen chloride, resulting in giving the desired compound. According to the process of the present invention, therefore, the desired compound can be prepared quantitatively without supplying hydrogen chloride separately, using a large excess of an acetylating agent or cooling the reaction system which are needed in conventional processes.
  • acetic acid or a mixed solvent of acetic acid and acetic anhydride can be suitably used as a solvent.
  • the amount of acetic anhydride may be about one-tenth of the amount of acetic acid or may be increased to several times of the amount of acetic acid.
  • the mixing ratio of the mixed solvent can be appropriately selected according to the reaction temperature or a desired reaction time.
  • the amount of the solvent to be used is not particularly limited and, for example, the amount is sufficiently from about 1 to about 5 parts by weight per part by weight of the 3-hydroxy compound. Suitable amount of acetyl chloride to be used may vary according to the solvent, but are usually within 1 to 20 moles per mole of the 3-hydroxy compound.
  • acetyl chloride when only acetic acid is used as the solvent, it is preferred to use acetyl chloride in an amount of more than 1 mole, preferably 1.01 to 10 moles, more preferably 1.05 to 1.5 moles, per mole of the 3-hydroxy compound.
  • acetyl chloride when a mixture of acetic acid and acetic anhydride is used as the solvent, it is preferred to use acetyl chloride in an amount of not less than 1 mole, preferably 1 to 5 moles, more preferably 1 to 1.5 moles, per mole of the 3-hydroxy compound.
  • the process of the present invention can be carried out at from a low temperature with cooling, for instance 5°C, to a high temperature with heating, for instance 130°C, preferably from the room temperature to a refluxing temperature.
  • a low temperature with cooling for instance 5°C
  • a high temperature with heating for instance 130°C
  • a mixture of acetic acid and acetic anhydride is used as the solvent, it is preferred to carry out the process at 5° to 130°C, more preferably 10° to 110°C.
  • the 3-hydroxy compound which is the starting material of the present invention there are four stereoisomers owing to asymmetric carbon atoms at the 2-position and the 3-position. Since the process of the present invention can be carried out without racemization, the desired compound having an optical activity can be obtained from the 3-hydroxy compound having the corresponding optical activity.
  • Isolation of the desired compound after the completion of the reaction can be easily carried out according to the conventional methods such as recrystallization after distilling the reaction solvent away.
  • the desired compound can be obtained in a high yield in one step without carrying out another step to obtain the hydrochloride after the acetylation or adding hydrochloric acid to a reaction system, since acetyl chloride acts as not only an acetylating agent but also a supplier of hydrogen chloride.
  • the process of the present invention therefore, has an industrially excellent advantage that the desired compound can be obtained by a simple operation in a high yield, compared with other conventional methods.
  • two steps namely a step for the acetylation and a step for the formation of the hydrochloride, are required to be carried out separetely in the process (1) described in Japanese Examined Patent Publication No. 813/1972 and No. 13038/1978, the desired compound can be obtained in one step in the present invention.
  • Example 1 The procedure of Example 1 was repeated except that the reaction was carried out at 70° - 80°C for 3 hours with stirring and 97 % ethanol was used for the recrystallization to give 8.45 g of hydrochloride of the d-cis-3-acetoxy compound. yield: 94 %
  • Example 2 The procedure of Example 1 was repeated except for the followings.
  • As reactants 50 g (0.13 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 12.7 g (0.16 mole) of acetyl chloride were used.
  • the reaction was carried out at 60°C for 3 hours with stirring in a mixed solvent of 81 ml of acetic acid and 19 ml of acetic anhydride and 97 % ethanol was used for the recrystallization.
  • 55.9 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained. yield: 92 %
  • Example 1 The procedure of Example 1 was repeated except for the followings.
  • As reactants 50 g (0.13 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 10.8 g (0.13 mole) of acetyl chloride were used.
  • the reaction was carried out at 100° - 110°C for 6 hours with stirring in a mixed solvent of 50 ml of acetic acid and 50 ml of acetic anhydride and 97 % ethanol was used for the recrystallization.
  • 53.7 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained. yield: 89 %
  • Example 1 The procedure of Example 1 was repeated except for followings.
  • As reactants 50 g (0.13 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 12.7 g (0.16 mole) of acetyl chloride were used.
  • the reaction was carried out at 60°C for 3 hours with stirring in a mixed solvent of 25 ml of acetic acid and 75 ml of acetic anhydride and 97 % ethanol was used for the recrystallization.
  • 54.7 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained. yield: 90.4 %

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Cardiology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Diaphragms For Electromechanical Transducers (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

A process for preparing hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1 ,5-benzothiazepin-4(5H)-one which comprises reacting 3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1 ,5-benzothiazepin-4(5H)-one with acetyl chloride in acetic acid or a mixed solvent of acetic acid and acetic anhydride. According to the process, hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1 ,5-benzothiazepin-4(5H)-one is readily obtained in one step.

Description

  • The present invention relates to a process for preparing hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one which is useful as a medicinal compound.
  • Hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (hereinafter referred to as desired compound), particularly, d-cis form thereof is a medicinal compound useful as a coronary vasodilator and an anti-hypertensive agent. Hitherto, there have been known some processes for preparing the desired compound. Examples of these processes are, for instance, (1) a process wherein 3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (hereinafter referred to as 3-hydroxy compound) is reacted with an acetylating agent such as acetic anhydride with heating to give 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (hereinafter referred to 3-acetoxy compound) according to a conventional method and then the resulting 3-acetoxy compound is treated with ethanolic hydrogen chloride (or methanolic hydrogen chloride) (see Japanese Examined Patent Publication No. 813/1972 and No. 18038/1978), (2) a process wherein the 3-hydroxy compound is reacted with acetic anhydride in the presence of hydrochloric acid in one step (see Japanese Unexamined Patent Publication No. 132876/1987) and the like.
  • However, in the process (1), two steps, namely, a step for the acetylation and a step for the formation of hydrochloride, are required to be carried out separately, although the acetylation can be suitably carried out in the absence of water. On the other hand, in the process (2), hydrochloric acid must be at first added with cooling and then the acetylation is carried out with heating, since heat is generated on the addition of hydrochloric acid (aqueous solution of hydrogen chloride) used as a supplier of hydrogen chloride. The operations in the method (2) are, therefore, complicated. Further, it is always required in the method (2) to use a large exess of acetic anhydride for removing water existing in the reaction system, which is introduced on the addition of hydrochloric acid, since the acetylation cannot be completed in the presence of water.
  • An object of the invention is to provide a process for simply preparing the desired compound from the 3-hydroxy compound in one step without cooling the reaction system or using a large excess of an acetylating agent.
  • This and the other objects of the present invention will become apparent from the description hereinafter.
  • It has now been found that a process for preparing hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one which comprises reacting 3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one with acetyl chloride in acetic acid or a mixed solvent of acetic acid and acetic anhydride overcomes the defects of the above-mentioned conventional processes.
  • The above-mentioned process of the present invention is established based upon a novel knowledge that acetyl chloride acts as not only an acetylating agent for the 3-hydroxy compound but also a supplier of hydrogen chloride, resulting in giving the desired compound. According to the process of the present invention, therefore, the desired compound can be prepared quantitatively without supplying hydrogen chloride separately, using a large excess of an acetylating agent or cooling the reaction system which are needed in conventional processes.
  • In the process of the present invention, acetic acid or a mixed solvent of acetic acid and acetic anhydride can be suitably used as a solvent. As to the mixing ratio of the mixed solvent, the amount of acetic anhydride may be about one-tenth of the amount of acetic acid or may be increased to several times of the amount of acetic acid. The mixing ratio of the mixed solvent can be appropriately selected according to the reaction temperature or a desired reaction time. The amount of the solvent to be used is not particularly limited and, for example, the amount is sufficiently from about 1 to about 5 parts by weight per part by weight of the 3-hydroxy compound. Suitable amount of acetyl chloride to be used may vary according to the solvent, but are usually within 1 to 20 moles per mole of the 3-hydroxy compound. For example, when only acetic acid is used as the solvent, it is preferred to use acetyl chloride in an amount of more than 1 mole, preferably 1.01 to 10 moles, more preferably 1.05 to 1.5 moles, per mole of the 3-hydroxy compound. On the other hand, when a mixture of acetic acid and acetic anhydride is used as the solvent, it is preferred to use acetyl chloride in an amount of not less than 1 mole, preferably 1 to 5 moles, more preferably 1 to 1.5 moles, per mole of the 3-hydroxy compound.
  • The process of the present invention can be carried out at from a low temperature with cooling, for instance 5°C, to a high temperature with heating, for instance 130°C, preferably from the room temperature to a refluxing temperature. Especially, when only acetic acid is used as the solvent, it is preferred to carry out the process at 10° to 110°C, more preferably 40° to 80°C. On the other hand, when a mixture of acetic acid and acetic anhydride is used as the solvent, it is preferred to carry out the process at 5° to 130°C, more preferably 10° to 110°C.
  • In case that a mixed solvent of acetic acid and acetic anhydride is used in the present invention, the reaction is accelerated and the solvent is prevented from freezing when temperature lowering.
  • With respect to the 3-hydroxy compound which is the starting material of the present invention, there are four stereoisomers owing to asymmetric carbon atoms at the 2-position and the 3-position. Since the process of the present invention can be carried out without racemization, the desired compound having an optical activity can be obtained from the 3-hydroxy compound having the corresponding optical activity.
  • Isolation of the desired compound after the completion of the reaction can be easily carried out according to the conventional methods such as recrystallization after distilling the reaction solvent away.
  • As indicated in the following Examples, according to the process of the present invention, the desired compound can be obtained in a high yield in one step without carrying out another step to obtain the hydrochloride after the acetylation or adding hydrochloric acid to a reaction system, since acetyl chloride acts as not only an acetylating agent but also a supplier of hydrogen chloride.
  • The process of the present invention, therefore, has an industrially excellent advantage that the desired compound can be obtained by a simple operation in a high yield, compared with other conventional methods. For example, while two steps, namely a step for the acetylation and a step for the formation of the hydrochloride, are required to be carried out separetely in the process (1) described in Japanese Examined Patent Publication No. 813/1972 and No. 13038/1978, the desired compound can be obtained in one step in the present invention. Further, while a large excess of acetic anhydride is required to be used in order to remove water existing in the reaction system, which is intruduced on the addition of hydrochloric acid (aqueous solution of hydrogen chloride), from the reaction system in the process (2) described in Japanese Unexamined Patent Publication No. 132876/1987, only 1 mole or a little more than 1 mole of acetyl chloride per mole of the 3-hydroxy compound may he sufficiently used in the present invention, which does not require the addition of hydrochloric acid with cooling, to obtain the desired compound in a high yield.
  • The present invention is more specifically described and explained by means of the following Experimental Examples and Examples.
    • Experimental Example 1
  • [Effect of a solvent for the acetylation on conversion rate]
  • In 200 ml of each solvent described in Table 2 were mixed 25 g of the d-cis-3-hydroxy compound and 5.8 g of acetyl chloride (1.1 moles per mole of the d-cis-3-hydroxy compound) and each mixture was stirred at 30°C for 2 hours. Conversion rate to the desired compound was determined by high performance liquid chromatography. The results are shown in the following Table 2. When acetic acid or a mixed solvent of acetic acid and acetic anhydride was used, the desired compound was obtained in a significantly high conversion rate compared with those in case of using other solvents.
    Figure imgb0001
    • Example 1
  • In 15 ml of acetic acid was dissolved 7.45 g (0.02 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one with heating. Then thereto was added 1.71 g (0.022 mole) of acetyl chloride at 20°C and the mixture was stirred at room temperature for 72 hours. After the reaction, acetic acid was distilled away and the residue was recrystallized from ethanol to give 7.53 g of hydrochloride of d-cis-3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one.
       yield: 83 %
       m.p. : 213° - 214°C
    • Example 2
  • The procedure of Example 1 was repeated except that the reaction was carried out at 70° - 80°C for 3 hours with stirring and 97 % ethanol was used for the recrystallization to give 8.45 g of hydrochloride of the d-cis-3-acetoxy compound.
       yield: 94 %
  • Physical properties of the obtained compound coincided with those of the desired compound in Example 1.
    • Example 3
  • The procedure of Example 1 was repeated except for the followings. As reactants, 50 g (0.13 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 12.7 g (0.16 mole) of acetyl chloride were used. The reaction was carried out at 60°C for 3 hours with stirring in a mixed solvent of 81 ml of acetic acid and 19 ml of acetic anhydride and 97 % ethanol was used for the recrystallization. Thus 55.9 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained.
       yield: 92 %
  • Physical properties of the obtained compound coincided with those of the desired compound in Example 1.
    • Example 4
  • The procedure of Example 1 was repeated except for the followings. As reactants, 50 g (0.13 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 10.8 g (0.13 mole) of acetyl chloride were used. The reaction was carried out at 100° - 110°C for 6 hours with stirring in a mixed solvent of 50 ml of acetic acid and 50 ml of acetic anhydride and 97 % ethanol was used for the recrystallization. Thus 53.7 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained.
       yield: 89 %
  • Physical properties of the obtained compound coincided with those of the desired compound in Example 1.
    • Example 5
  • The procedure of Example 1 was repeated except for followings. As reactants, 50 g (0.13 mole) of d-cis-3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and 12.7 g (0.16 mole) of acetyl chloride were used. The reaction was carried out at 60°C for 3 hours with stirring in a mixed solvent of 25 ml of acetic acid and 75 ml of acetic anhydride and 97 % ethanol was used for the recrystallization. Thus 54.7 g of the hydrochloride of the d-cis-3-acetoxy compound was obtained.
       yield: 90.4 %
  • Physical properties of the obtained compound coincided with those of the desired compound in Example 1.

Claims (5)

  1. A process for preparing the hydrochloride of 3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one which comprises reacting 3-hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one with acetyl chloride in acetic acid or a mixed solvent of acetic acid and acetic anhydride.
  2. The process of Claim 1, wherein 1 to 20 moles of acetyl chloride is used per mole of a 3-hydroxy-1,5-benzothiazepine derivative which is a starting material.
  3. The process of claim 1, wherein the reaction is carried out in acetic acid by using 1.01 to 10 moles of acetyl chloride per mole of a 3-hydroxy-1,5-benzothiazepine derivative which is a starting material.
  4. The process of claim 1, wherein the reaction is carried out in a mixed solvent of acetic acid and acetic anhydride by using 1 to 5 moles of acetyl chloride per mole of a 3-hydroxy-1,5-benzothiazepine derivative which is a starting material.
  5. The process of Claim 1, 2, 3 or 4 wherein the d-cis form of 3-hydroxy-1,5-benzothiazepine derivative is used as a starting material.
EP91120269A 1990-11-29 1991-11-27 Process for preparing 1,5-benzothiazepine derivative Expired - Lifetime EP0488210B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP336010/90 1990-11-29
JP33601090 1990-11-29

Publications (2)

Publication Number Publication Date
EP0488210A1 EP0488210A1 (en) 1992-06-03
EP0488210B1 true EP0488210B1 (en) 1994-06-22

Family

ID=18294763

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91120269A Expired - Lifetime EP0488210B1 (en) 1990-11-29 1991-11-27 Process for preparing 1,5-benzothiazepine derivative

Country Status (15)

Country Link
US (1) US5169946A (en)
EP (1) EP0488210B1 (en)
JP (1) JPH0822856B2 (en)
KR (1) KR0133056B1 (en)
CN (1) CN1031342C (en)
AT (1) ATE107638T1 (en)
AU (1) AU634108B2 (en)
DE (1) DE69102614T2 (en)
DK (1) DK0488210T3 (en)
ES (1) ES2059020T3 (en)
FI (1) FI104173B (en)
HK (1) HK174295A (en)
HU (1) HU209830B (en)
IE (1) IE914135A1 (en)
IL (1) IL100157A (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5705638A (en) * 1995-12-05 1998-01-06 Tanabe Seiyaku Co., Ltd. Process for preparing optically active 3-hydroxy-1,5-benzothiazepine derivative and intermediate therefor
EP0778272B1 (en) * 1995-12-05 1998-12-23 Tanabe Seiyaku Co., Ltd. Optically active benzothiazepine compounds and process for preparing the same

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3562257A (en) * 1967-10-28 1971-02-09 Tanabe Seiyaku Co Benzothiazepine derivatives
FR2360124A1 (en) * 1976-07-30 1978-02-24 Amiens Const Electro Mecan Heating power switching control in domestic appliance - uses micromotor actuated only on reception of signal detecting appliance operating conditions
US4590188A (en) * 1984-02-18 1986-05-20 Tanabe Seiyaku Co., Ltd. 1,5-benzothiazepine derivatives and their pharmaceutical use
JPS62132876A (en) * 1985-12-04 1987-06-16 Kohjin Co Ltd Production of 1,5-benzothiazepine derivative
JPH085869B2 (en) * 1990-03-08 1996-01-24 田辺製薬株式会社 Process for producing 1,5-benzothiazepine derivative

Also Published As

Publication number Publication date
US5169946A (en) 1992-12-08
CN1062141A (en) 1992-06-24
AU634108B2 (en) 1993-02-11
EP0488210A1 (en) 1992-06-03
ATE107638T1 (en) 1994-07-15
DE69102614T2 (en) 1994-11-24
IL100157A0 (en) 1992-08-18
DK0488210T3 (en) 1994-08-01
HK174295A (en) 1995-11-24
HU913713D0 (en) 1992-02-28
KR920009808A (en) 1992-06-25
FI915625A (en) 1992-05-30
IE914135A1 (en) 1992-06-03
FI104173B1 (en) 1999-11-30
HU209830B (en) 1994-11-28
CN1031342C (en) 1996-03-20
ES2059020T3 (en) 1994-11-01
KR0133056B1 (en) 1998-04-17
FI915625A0 (en) 1991-11-28
JPH0822856B2 (en) 1996-03-06
HUT61988A (en) 1993-03-29
AU8825391A (en) 1992-06-04
JPH0543564A (en) 1993-02-23
IL100157A (en) 1995-12-08
DE69102614D1 (en) 1994-07-28
FI104173B (en) 1999-11-30

Similar Documents

Publication Publication Date Title
JP2791046B2 (en) Method for producing methylene derivative of androsta-1,4-diene-3,17-dione
DE3472407D1 (en) Process for preparing cyanohydrine derivatives containing phosphorus
EP0488210B1 (en) Process for preparing 1,5-benzothiazepine derivative
EP1104765B2 (en) Process for preparing n,n,6- trimethyl-2 -(4-methylphenyl)- imidazo-[1,2-a] -pyridine-3- acetamide and salts thereof
US5256793A (en) Triazolinone ring formation in tert-butanol
EP0645365B1 (en) Process for producing 2-fluoroisobutyric acid or ester thereof
EP0395323B1 (en) Process for preparing 1,5-benzothiazepine derivatives
JPH0745474B2 (en) Method for producing 1-hydroxy-2-pyridone
JPH04234866A (en) Production of 1,5-benzothiazepine derivative
CA2056129C (en) Process for preparing 1,5-benzothiazepine derivative
JPS597719B2 (en) Production method of cytidine derivatives
US5260457A (en) Process for producing coumarin and derivative thereof
IE57288B1 (en) Preparation process of acemetacin
US6225491B1 (en) Method for preparing certain acetonitriles
US4456766A (en) Process for the production of N-acetyl-2,3-dehydro-aminocarboxylic acid esters
JPH0641176A (en) 2-alkylacryloyloxyethyl-beta-d-galactoside compound and its production
JP2000229930A (en) Production of cyanoacetate ester
JP3235232B2 (en) Method for producing thiocarbamate
US6268512B1 (en) Process for producing 3-methyl-2-oxoindoline
JPS60116677A (en) Production of benzothiazepine derivative
JPH0354939B2 (en)
ES8700221A1 (en) Process for the preparation of alpha-hydroxy-alkanoic acids.
HU195489B (en) Process for producing 1,2-diphenyl-4 brackets open /2-phenyl-sulfinyl/-ethyl brackets closed-3,5-pyrazolidindione
JPH10310567A (en) Crystallization of 3-amino-2-(n-alkoxycarbonyl) aminopropionic acid ester-substituted benzenesulfonic acid salt
JPH08277251A (en) Production of dimethylformamide dimethyl acetal

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17P Request for examination filed

Effective date: 19920709

17Q First examination report despatched

Effective date: 19930811

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

REF Corresponds to:

Ref document number: 107638

Country of ref document: AT

Date of ref document: 19940715

Kind code of ref document: T

ITF It: translation for a ep patent filed

Owner name: ST. DR. CAVATTONI ING. A. RAIMONDI

REF Corresponds to:

Ref document number: 69102614

Country of ref document: DE

Date of ref document: 19940728

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

ET Fr: translation filed
REG Reference to a national code

Ref country code: GR

Ref legal event code: FG4A

Free format text: 3012319

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2059020

Country of ref document: ES

Kind code of ref document: T3

EAL Se: european patent in force in sweden

Ref document number: 91120269.5

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20101110

Year of fee payment: 20

Ref country code: AT

Payment date: 20101110

Year of fee payment: 20

Ref country code: NL

Payment date: 20101116

Year of fee payment: 20

Ref country code: FR

Payment date: 20101123

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20101124

Year of fee payment: 20

Ref country code: CH

Payment date: 20101112

Year of fee payment: 20

Ref country code: LU

Payment date: 20110110

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20101020

Year of fee payment: 20

Ref country code: IT

Payment date: 20101117

Year of fee payment: 20

Ref country code: GR

Payment date: 20101020

Year of fee payment: 20

Ref country code: GB

Payment date: 20101124

Year of fee payment: 20

Ref country code: SE

Payment date: 20101111

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20101126

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 69102614

Country of ref document: DE

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 69102614

Country of ref document: DE

BE20 Be: patent expired

Owner name: *TANABE SEIYAKU CO. LTD

Effective date: 20111127

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: NL

Ref legal event code: V4

Effective date: 20111127

REG Reference to a national code

Ref country code: DK

Ref legal event code: EUP

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20111126

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20111127

REG Reference to a national code

Ref country code: GR

Ref legal event code: MA

Ref document number: 940401378

Country of ref document: GR

Effective date: 20111128

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK07

Ref document number: 107638

Country of ref document: AT

Kind code of ref document: T

Effective date: 20111127

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20120220

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20111126

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20111128

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20111128